Macmillan, J. published an article in 1959, the title of the article was Griseofulvin. XVI. Synthesis of compounds related to griseofulvin.Related Products of 53724-96-2 And the article contains the following content:
Racemic spirans related to griseofulvin (I) were prepared by condensation between coumarones and dibromoalkanes (II). The presence of the grisan ring synthesis in I was confirmed by synthesis of 7-chloro-4,6-dimethoxy-2′-methylgrisan-3-one (III), which was shown to be the racemate of the l,d-stereoisomer, obtained by degrading the l,d-diastereoisomer of I (the prefixes denote the configuration of the 2 asym. centers, the spiran center preceding; I is the d,d-stereoisomer, inversion of the spiran center giving the l,d-diastereoisomer). The synthesis of racemates of some non-spiran oxidation products, and improved preparations of some II, were also described. (All m.ps. are corrected; ultraviolet spectra determined in EtOH solution) NaBr (109 g.) and 137 ml. concentrated H2SO4 in 125 ml. H2O kept at 30° during the gradual addition of 43 g. tetrahydro-2-methylfuran, the mixture boiled 2 hrs., steam distilled, the distillate extracted with Et2O, and the extract fractionated gave 103 g. CH2Br(CH2)2CHBrMe (IV), b25 98-9°, n15D 1.516. (a) CH2Br(CH2)3CHBrMe (V), b100 153-5°, was prepared in 1.2% over-all yield according to Perkin [J. Chem. Soc. 51, 702(1887)]. (b) PBr3 (182 g.) and then 120 g. Br added in portions to 140 g. 1-benzoyl-2-methylpiperidine, m. 46°, at 0° with shaking, the product distilled in vacuo until the distillate became yellow, the distillate shaken with 500 g. ice, the mixture extracted with petr. ether (VI), the extract washed with aqueous Na2CO3, H2O, and concentrated H2SO4 until the washings were colorless, concentrated, and the residue distilled gave 103 g. V, b23 121-4°. Dry HCl passed into a solution of 72.0 g. m-C6H4(OH)2, 48 g. CH2ClCN, and 48 g. ZnCl2 in dry Et2O 2 hrs. at room temperature, after 1 hr. the precipitate filtered off, washed with Et2O, hydrolyzed 1 hr. at 70° with 5 l. H2O, the mixture cooled, and the product crystallized (PhMe) gave 85 g. 2,4-(HO)2C6H3COCH2Cl (VII), in. 132-3°. (a) VII (30 g.) in 300 ml. Et2O treated with CH2N2-Et2O and the precipitate crystallized (EtOH) gave 31 g. 5,2-MeO(ClCH2CO)C6H3OH (VIII), m. 116-17°. (b) Powd. AlCl3 (9 g.) added to 8.0 g. m-C6H4(OMe)2 and 6.5 g. CH2ClCOCl in 30 ml. CS2, after 1 hr. CS2 decanted from a red oil, the oil treated with 30 ml. ice-cold H2O and 20 ml. concentrated HCl, steam distilled, and the steam distillate worked up gave 3.9 g. VIII, m. 116-17°. (a) 6-Hydroxy-3-coumaranone (5.0 g.) in 2 l. C6H6 and excess CH2N2-Et2O kept 18 hrs. and the neutral product recovered gave 4.2 g. 6-methoxy compound (IX), m. 124-5°, ν 1710 cm.-1, λ 318, 268, 233, 208 mμ (log ε 4.00, 4.12, 4.05, 4.29). (b) VIII (3.0 g.) and 3.0 g. NaOAc in 150 ml. EtOH heated 2 hrs. and the product crystallized gave 2.2 g. IX, m. 124-5°. IX (0.82 g.) in 50 ml. C6H6 added (during 30 min.) simultaneously with 1.15 g. IV in 50 ml. C6H6 to a stirred and refluxing suspension of 1.4 g. Me3COK (X) in 50 ml. C6H6, the mixture refluxed 3 hrs., cooled, the filtered solution washed with aqueous NaOH and H2O, evaporated, the residue chromatographed in C6H6 on Al2O3, a blue band eluted with C6H6, the recovered oil (300 mg.) rechromatographed in VI, eluted with 20:1 Et2O-VI, and the gum crystallized from petr. ether gave 36 mg. 6-methoxy-3-oxocoumaran-2-spiro-1′-(2′-methylcylopentane), m. 167-8° (sublimation in vacuo and recrystallization from EtOH), ν 1712 cm.-1, λ 318, 267, 233, 208 mμ (log ε 4.01, 4.12, 4.05, 4.29). 7-Chloro-4,6-dimethoxy-3-coumaranone (XI) (2.29 g.) in 50 ml. C6H6 treated as above with 2.8 g. X in 50 ml. C6H6, refluxed 5 hrs., cooled, filtered, the filtrate extracted with aqueous NaOH, and the extract acidified gave 60 mg. 3,2,4,6-Cl(HO)(MeO)2C6HAc, m. 189-91°; the semisolid (recovered from the neutral fraction) repeatedly extracted with VI, the solid (400 mg.) recovered from the extract sublimed at 110°/10-4 mm., and the sublimate crystallized (EtOH) gave 7-chloro-4,6-dimethoxy-3-oxocoumaran-2-spirocydopentane, m. 192-3°, ν 1717 cm.-1, λ 331, 322, 289, 238, 213 mμ (log ε 3.68, 3.69, 4.30, 4.20, 4.37); the VI-insoluble material chromatographed and sublimed gave 1.08 g. XI, m. 212-14°. XI (2.29 g.) in 50 ml. C6H6 condensed with 2.31 g. Br(CH2)5Br in 50 ml. C6H6 in the presence of 2.8 g. X in 50 ml. C6H6 as above, the residual gum treated with C6H6-VI, the precipitated solid (120 mg.) sublimed at 130°/10-4 mm., and the sublimate recrystallized (EtOH) gave 70 mg. 7-chloro-4,6-dimethoxygrisan-3-one, m. 176-7°, ν 1715 cm.-1; 1.20 g. XI was recovered from the C6H6-VI mother liquor. XI (2.90 g.) condensed as above with 2.44 g. V in the presence of 2.80 g. X (identical volumes C6H6 used), refluxed 1.5 hrs., cooled, the filtered solution washed with aqueous NaOH, concentrated to 5 ml., diluted with 5 ml. VI, and the solution kept at 0° deposited 112 mg. precipitate (XII); the gum recovered from the mother liquor chromatographed in C6H6 on Al2O3 and eluted with C6H6 gave, from a yellow band, 40 mg. gum, which, sublimed (120-30°/10-4 mm.) and crystallized (EtOH), afforded 25 mg. compound (XIII), and, from a blue band, 340 mg. gum, which, crystallized (C6H6-VI), yielded 295 mg. compound (XIV); XII, XIII, and XIV combined, sublimed (110-20°/10-4 mm.), and crystallized (EtOH) gave 405 mg. III, m. 157-8°, λ 331, 322, 289, 238, 212 mμ (log ε 3.67, 3.70, 4.33, 4.20, 4.41). XI (11.45 g.) in 200 ml. C6H6 condensed with 12.25 g. MeCHBr(CH2)2COBr in 100 ml. C6H6 in the presence of 14 g. X in 100 ml. C6H6 as above, the C6H6 solution extracted with aqueous NaOH, evaporated, and chromatographed gave 1.3 g. 7-chloro-4,6-dimethoxycoumaron-3-yl- γ-bromovalerate, m. 124°, ν 1760, 1623, 1609 cm.-1, λ 265 and 219 mμ (log ε 4.18, 4.62). XI (4.2 g.) in 200 ml. dioxane treated at 46° with 2.1 g. MeCH:CHCO2Me (XV) and 8.0 ml. N MeONaMeOH, kept 6 hrs. at 55-60° and 2 days at room temperature, the filtered solution treated with 5 ml. AcOH and C, filtered, and the filtrate evaporated in vacuo; the residue dissolved in 150 ml. C6H6, the solution washed with H2O, dried, chromatographed on Al2O3, eluted with 100:1 C6H6-MeOH, the recovered product distilled (170-200°/10-4 mm.) on to a cold finger, and the material crystallized gave 1.0 g. product (XVI); the material recovered from the mother liquor extracted with Me2CO gave 0.5 g. product (XVII); XVI and XVII combined and washed with Me2CO gave 1.00 g. α-ester (XVIII), Me 7-chloro-4,6-dimethoxy-3-oxocoumaran-2-β-butyrate, m. 152-4° (C6H6-VI); the gum recovered from the mother liquors fractionally crystallized (Et2O) gave 0.8 g. impure material and 0.90 g. β-XVIII, m. 83-6°, m.p. not depressed with (-)-β-XVIII prepared from I (see below). β-XVIII (100 mg.), 0.5 g. anhydrous K2CO3, and 10 ml. Me2CO refluxed 7 hrs. and the product fractionally crystallized (C6H6-VI) gave 36 mg. α-XVIII, m. 150-2°; crystallization of the more soluble fractions from Et2O gave 41 mg. β-XVIII, m. 83-5°. Similar results were obtained with α-XVIII. (1) α-XVIII (561 mg.) and 25 ml. N HCl boiled 3 hrs. (20 ml. H2O added after 2.5 hrs.), the precipitate (495 mg.) filtered off, and washed with H2O gave (-)-7-chloro-4,6-dimethoxy-3-oxocoumaran-2-β-butyric acid (XIX), m. 154-62° (decomposition). (2) Hydrolysis of 500 mg. β-XVIII in the same way gave 460 mg. XIX. XIX treated with CH2N2 gave a mixture separated by crystallization into 47 mg. α-XVIII, m. 142-50°, and 38 mg. β-XVIII, m. 82-5°. XIX (234 mg.) and 10 ml. N NaOH boiled 4 hrs., cooled, filtered, the filtrate acidified, the precipitate (123 mg.) collected, and crystallized (EtOAc) gave 7-chloro-6-hydroxy-4-methoxy-3-oxocoumaran-2-β-butyric acid, m. 212-14° (decomposition), ν (CHCl3) 1701 and 1737 cm.-1 XIX (134 mg.) in 10 ml. N Na2CO3 treated at 1-2° during 1.5 hrs. with 3.0 ml. 4.5% aqueous KMnO4, the mixture kept 1.5 hrs. at 0°, excess decomposed with SO2, the filtered solution acidified with HCl, the gummy product (isolated with Et2O) treated with a little Et2O, and the resultant solid (85 mg.) crystallized from EtAc-petr. ether gave the 2-OH derivative (XX), m. 189-90° (decomposition). XX (85 mg.), 0.3 ml. Ac2O, and 0.7 ml. C5H5N kept 3 days at 35°, diluted with H2O at 0°, and the product washed with aqueous NaHCO3 and H2O gave the lactone (XXI), m. 223-4° (EtOAc). XXI was also obtained by subliming XX at 190-210°/10-4 mm. N MeONa-MeOH (2.0 ml.) added to 1.94 g. 4,6-dimethoxy-3-coumaranone (XXII) and 1.00 g. XV in 40 ml. dioxane at 24°, after 24 hrs. the mixture acidified with AcOH, evaporated in vacuo, the residue taken up in Et2O, the solution washed with aqueous NaHCO3, and H2O, evaporated, the oily product chromatographed in Et2O on Al2O3, and a blue band eluted with 100:1 Et2O-MeOH gave 1.7 g. sirup (XXIII); 2.3 g. XXIII from several experiments kept with Et2O gave 1.0 g. α-ester, Me 4,6-dimethoxy-3-oxocoumaran-2-β-butyric acid (XXIV) Me ester (XXV), m. 88-9° (C6H6Et2O); the sirup from the Et2O mother liquor distilled (180-210°/10-3 mm.) gave essentially β-XXV, sirup. 2N EtONa-EtOH (0.43 ml.) added to 1.00 g. XXII and 0.59 g. MeCH:CHCO2Et in 18 ml. dioxane at 20° after 48 hrs. the mixture filtered, the filtrate acidified with AcOH, the product recovered, chromatographed, eluted like XXV, and the oil (1.00 g.) distilled (190°/10-3 mm.) gave XXIV Et ester (XXVI), oil. XXVI (1.9 g.) and 20 ml. 3N HCl boiled 5 hrs., the cooled mixture made alk., washed with Et2O, acidified, the product (1.19 g.) extracted with Et2O, and the extract distilled (200°/10-3 mm.) gave XXIV, containing a phenolic impurity. XXIV (350 mg.) in 22 ml. N Na2CO3 treated at 1-2° during 2 hrs. with 7.6 ml. 4.5% aqueous KMnO4 and worked up gave 70 mg. 2-OH derivative (XXVII), m. 169-73° (decomposition). Dehydration of XXVII as above gave the lactone (XXVIII), m. 150-1° (EtOAc-petr. ether). An ice-cold suspension of 525 mg. XXVI in 30 ml. N Na2CO3 treated dropwise with 5% aqueous KMnO4 (only a few drops decolorized), 25 ml. dioxane added, 10.0 ml. 5% aqueous KMnO4, added in 1 hr., the mixture kept overnight at 0°, decolorized with SO2, filtered, the filtrate and Me2CO washings of the filter cake evaporated in vacuo, aqueous NaOH added to the residue, the mixture extracted with Et2O (0.2 g. XXVI recovered from the extract), acidified, the product extracted with Et2O, and crystallized (Et2O and then EtAc) gave 34 mg. XXVIII, m. 150-1°. (-)-XIX from I gave (-)-β-XVIII, m. 96-8° (Et2O), [α]22D -19° ± 3° (c 0.84, Me2CO). The experimental process involved the reaction of Ethyl 6-methoxy-3-methylbenzofuran-2-carboxylate(cas: 53724-96-2).Related Products of 53724-96-2
Ethyl 6-methoxy-3-methylbenzofuran-2-carboxylate(cas:53724-96-2) belongs to benzofuran. Benzofuran is the “parent” of many related compounds with more complex structures. For example, psoralen is a benzofuran derivative that occurs in several plants. Related Products of 53724-96-2
Referemce:
Benzofuran – Wikipedia,
Benzofuran | C8H6O – PubChem